Shu Meng, Jia Yiying, Zhang Shuwei, Zou Bangyu, Ying Zhaoxin, Gao Xu, Fang Ziyu, Gao Xiaofeng
Department of Urology, Changhai Hospital of Shanghai, Naval Medical University, Shanghai 200433, China.
Shanghai Key Laboratory of Cell Engineering, Shanghai 200433, China.
Biomolecules. 2025 Jul 28;15(8):1090. doi: 10.3390/biom15081090.
Nephrolithiasis, predominantly driven by calcium oxalate (CaOx) crystal deposition, poses a significant global health burden due to its high prevalence and recurrence rates and limited preventive/therapeutic options. Recent research has underscored a pivotal role for macrophage polarization in nephrolithiasis pathogenesis. Pro-inflammatory phenotype macrophages exacerbate crystal-induced injury and foster stone formation by amplifying crystal adhesion via an NF-κB-IL-1β positive-feedback axis that sustains ROS generation and NLRP3 inflammasome activation, whereas anti-inflammatory phenotype macrophages facilitate crystal clearance and tissue repair. We have summarized the research on treating nephrolithiasis and related renal injury by targeting macrophage polarization in recent years, including therapeutic approaches through pharmacological methods, epigenetic regulation, and advanced biomaterials. At the same time, we have critically evaluated the novel therapeutic strategies for macrophage reprogramming and explored the future development directions of targeting macrophage reprogramming for nephrolithiasis treatment, such as using single-cell/spatial omics to reveal the heterogeneity of macrophages in the stone microenvironment, chimeric antigen receptor macrophages (CAR-Ms) as a potential therapy for specific crystal phagocytosis in certain areas, and multi-omics integration to address inter-patient immune differences. This review highlights that macrophage reprogramming is a transformative frontier in nephrolithiasis management and underscores the need for further research to translate these molecular insights into effective clinical applications.
肾结石主要由草酸钙（CaOx）晶体沉积驱动，因其高发病率、高复发率以及有限的预防/治疗选择，给全球健康带来了重大负担。最近的研究强调了巨噬细胞极化在肾结石发病机制中的关键作用。促炎表型巨噬细胞通过经由维持ROS生成和NLRP3炎性小体激活的NF-κB-IL-1β正反馈轴放大晶体粘附，加剧晶体诱导的损伤并促进结石形成，而抗炎表型巨噬细胞则促进晶体清除和组织修复。我们总结了近年来通过靶向巨噬细胞极化治疗肾结石及相关肾损伤的研究，包括通过药理学方法、表观遗传调控和先进生物材料的治疗方法。同时，我们批判性地评估了巨噬细胞重编程的新型治疗策略，并探索了靶向巨噬细胞重编程治疗肾结石的未来发展方向，例如使用单细胞/空间组学揭示结石微环境中巨噬细胞的异质性，嵌合抗原受体巨噬细胞（CAR-Ms）作为特定区域特异性晶体吞噬的潜在疗法，以及多组学整合以解决患者间的免疫差异。本综述强调巨噬细胞重编程是肾结石管理中的一个变革性前沿领域，并强调需要进一步研究将这些分子见解转化为有效的临床应用。
